As part of the SAR profiling of the indole-oxoacetic piperazinyl benzamide class of HIV-1 attachment inhibitors, substitution at the C7 position of the lead 4-fluoroindole 2 with various 5- and 6-membered heteroaryl moieties was explored. Highly potent (picomolar) inhibitors of pseudotyped HIV-1 in a primary, cell-based assay were identified and select examples were shown to possess nanomolar inhibitory activity against M- and T-tropic viruses in cell culture. These C7-heteroaryl-indole analogs maintained the ligand efficiency (LE) of 2 and were also lipophilic efficient as measured by LLE and LELP. Pharmacokinetic studies of this class of inhibitor in rats showed that several possessed substantially improved IV clearance and half-lives compared to 2. Oral exposure in the rat correlated with membrane permeability as measured in a Caco-2 assay where the highly permeable 1,2,4-oxadiazole analog 13 exhibited the highest exposure.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.bmcl.2012.10.117 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Nuclear Factor Kappa B p65: A Possible Biomarker for Persistent Inflammation in HIV-1 Infection?
Cureus
October 2024
Microbiology, Sri Ramachandra Institute of Higher Education and Research, Sri Ramachandra Faculty of Allied Health Science, Chennai, IND.
Low-grade inflammation in people living with HIV (PWH) has become a significant contributor to the development of non-communicable diseases (NCDs) such as heart disease, stroke, and renal dysfunction. Though antiretroviral therapy (ART) has dramatically reduced mortality by limiting the emergence of opportunistic infections, it has not been successful in eliminating the remaining chronic, low-grade inflammation and activation that persists in the infected despite viral suppression and better CD4+ T cell count. Nonetheless, this relatively asymptomatic and subclinical chronic inflammation remains poorly understood and has become a major contributor to mortality in PWH.
View Article and Find Full Text PDFElectron tomography visualization of HIV-1 virions trapped by fusion inhibitors to host cells in infected tissues.
J Virol
November 2024
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA.
HIV-1 delivers its genetic material to infect a cell after fusion of the viral and host cell membranes, which takes place after the viral envelope (Env) binds host receptor and co-receptor proteins. Binding of host receptor CD4 to Env results in conformational changes that allow interaction with a host co-receptor (CCR5 or CXCR4). Further conformational rearrangements result in an elongated pre-hairpin intermediate structure in which Env is anchored to the viral membrane by its transmembrane region and to the host cell membrane by its fusion peptide.
View Article and Find Full Text PDFArticle Synopsis
- HIV-1 envelope glycoprotein (Env) structure affects the immune response, with "closed" forms evading certain antibodies while "open" forms are vulnerable to others.
- Infected CD4+ T cells show that downmodulation of CD4 occurs before HIV-1 mRNA expression, and these cells mainly express "closed" Envs, resistant to non-neutralizing antibodies (nnAbs).
- The study challenges the effectiveness of nnAbs in targeting productively infected cells for HIV-1 treatment, as attempts with nnAbs did not reduce viral replication in humanized mouse models.
Efficacy and safety of two fixed doses of ibalizumab plus optimized background regimen in treatment-experienced HIV-positive individuals.
J Acquir Immune Defic Syndr
September 2024
Theratechnologies Inc., Montréal, Québec, Canada.
Background: Sustained viral suppression in patients with multidrug-resistant (MDR) human immunodeficiency virus (HIV) infection remains difficult; accordingly, agents targeting different steps in the HIV life cycle are needed. Ibalizumab, a humanized immunoglobulin G4 monoclonal antibody, is a cluster of differentiation (CD4)-directed post-attachment inhibitor.
Methods: In this Phase IIb study, 113 individuals with MDR HIV-1 and limited treatment options were assigned an optimized background regimen (OBR) and randomized to either 800 mg ibalizumab every two weeks (q2wk; n=59) or 2,000 mg ibalizumab every four weeks (q4wk; n=54) up to Week 24.
Inflammatory Biomarker Reduction With Fostemsavir Over 96 Weeks in Heavily Treatment-Experienced Adults With Multidrug-Resistant HIV-1 in the BRIGHTE Study.
Open Forum Infect Dis
September 2024
ViiV Healthcare, Branford, Connecticut, USA.
Background: Fostemsavir, a first-in-class attachment inhibitor that binds to the viral envelope protein gp120, is approved for heavily treatment-experienced persons with HIV-1 with limited treatment options. We explored changes in immunologic and coagulopathy parameters in the BRIGHTE study: a phase 3 trial that evaluated fostemsavir plus optimized background therapy in heavily treatment-experienced adults with multidrug-resistant HIV-1.
Methods: CD4+ T-cell count, CD4+/CD8+ ratio, soluble CD14, soluble CD163, and D-dimer levels were measured through 96 weeks in participants with 1 or 2 fully active antiretroviral agents available at screening.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!